title: Identification of cis-elements and transcription factors regulating neuronal activity-dependent transcription of human BDNF gene.
abstract: Brain-derived neurotrophic factor (BDNF) is an important mediator of activity-dependent functions of the nervous system and its expression is dysregulated in several neuropsychiatric disorders. Regulation of rodent BDNF neuronal activity-dependent transcription has been relatively well characterized. Here, we have studied regulation of human BDNF (hBDNF) transcription by membrane depolarization of cultured mouse or rat primary cortical neurons expressing hBDNF gene or transfected with hBDNF promoter constructs, respectively. We identified an asymmetric E-box-like element, PasRE [basic helix-loop-helix (bHLH)-PAS transcription factor response element], in hBDNF promoter I and demonstrate that binding of this element by bHLH-PAS transcription factors ARNT2 (aryl hydrocarbon receptor nuclear translocator 2) and NPAS4 (neuronal PAS domain protein 4) is crucial for neuronal activity-dependent transcription from promoter I. We show that binding of CREB (cAMP response element-binding protein) to the cAMP/Ca(2+)-response element (CRE) in hBDNF promoter IV is critical for activity-dependent transcription from this promoter and that upstream stimulatory factor (USF) transcription factors also contribute to the activation by binding to the upstream stimulatory factor binding element (UBE) in hBDNF promoter IV. However, we report that full induction of hBDNF exon IV mRNA transcription is dependent on ARNT2 and NPAS4 binding to a PasRE in promoter IV. Finally, we demonstrate that CRE and PasRE elements in hBDNF promoter IX are required for the induction of this promoter by neuronal activity. Together, the results of this study have identified the cis-elements and transcription factors regulating neuronal activity-dependent transcription of human BDNF gene.
authors.affiliation: Institute of Gene Technology, Tallinn University of Technology, 12618 Tallinn, Estonia. priit.pruunsild@ttu.ee
authors.forename: Priit
authors.initials: P
authors.lastname: Pruunsild
authors.forename: Mari
authors.initials: M
authors.lastname: Sepp
authors.forename: Ester
authors.initials: E
authors.lastname: Orav
authors.forename: Indrek
authors.initials: I
authors.lastname: Koppel
authors.forename: Tõnis
authors.initials: T
authors.lastname: Timmusk
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D020013:Calcium Signaling / Q000235:genetics; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D016764:Cell Polarity / Q000235:genetics; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D014157:Transcription Factors